[Thesis]. Manchester, UK: The University of Manchester; 2018.
Drugs and other xenobiotic compounds exhibit different transformations upon entering
the human body, most often starting with an oxidative reaction involving P450 enzymes.
Hence, the effectiveness and half-life, and even the toxicity of these drugs is determined
in part to their metabolism. Thus, it is imperative to produce better models, either
experimental or theoretical, to facilitate the understanding and predict the behaviour
of these processes.
Herein, I present a computational study using hybrid quantum mechanics/molecular mechanics
(QM/MM) and density functional theory (DFT) methodologies to model enzymatic metabolism
reactions. The work particularly emphasises on the reactivity patterns of the active
species of cytochrome P450, i.e. Compound I or the iron(IV)-oxo heme cation radical
species, through the use of biomimetic models and enzymatic structures.
I initially started the work with a thorough benchmark study on the reproducibility
and limitations of DFT methods and compare a set of calculated free energy of activations
against experimental reaction rates for a biomimetic FeIVO model. In particular, I
focus on a range of density functional theory methods, basis sets, empirical dispersion
corrections and solvation as well as entropic effects on the free energy of activation.
Based on these studies a recommended set of methods and procedures is proposed.
Thereafter, a series of projects explore the reactivity of biomimetic models of Compound
I against a number of model substrates. Starting with a model of a carbene ligated
iron(IV)-oxo system that shows catalytic properties dramatically altered with respect
to P450 CpdI. Through DFT characterization and reactivity with a set of common substrates
I establish the electronic and catalytic differences. A subsequent set of projects
explore the chemistry of a set of iron(IV)-oxo biomimetic models of Compound I with
either a pure computational or a mixed computational-experimental approach. Sound
characterizations of the catalytic properties and mechanistic descriptions of such
systems are presented often with comparisons to P450-Compound I. A gas phase electron
deficient metalloporphyrin model, TPFFP+Ă˘Â˘ is explored giving comprehensive evidence
and rationalization into the distinctions between the mechanisms of aromatic vs aliphatic
hydroxylation with common aromatic substrates. Further experiments and modelling were
performed in a follow up project where a stable cationic intermediate is formed in
contrast to the more common radical intermediate chemistry as seen in CpdI with the
Following this investigations, a rather more applied set of projects is presented.
First the capabilities of a simplified P450 model are explored for the prediction
of toxic metabolic products and sites of metabolism (SOMs) derived from P450-oxidations
on a common phthalate derived substrate found frequently on cosmetic products and
pharmaceutical formulations, revealing reaches and limitations of this approach. Lastly,
a comprehensive DFT and QM/MM approach is employed to investigate the chemistry behind
the co-factor independent oxidation of nogalamycin, a naturally occurring antibiotic.
Thermochemical cycles, DFT models as well as QM/MM studies highlight possible oxidants
in the reaction mechanism and propose relevant factors affecting the chemical reaction.